We are graduate students and postdocs working on basic research in the neurosciences at Harvard University. We are excited about neuroscience and hope to convince you - whether you’ve never heard of brains or are a seasoned scientist - that brain research is one of the most fascinating areas of science today.

In 2015 The Danish Girl, Ruby Rose, Caitlyn Jenner, and Transparent paved the road for trans-visibility in mainstream media. This has brought a great deal of attention and debate to the medical and political scene, but a large gap still remains between policy making and our understanding of how trans-sexuality develops through childhood and adolescence, and how we can alleviate the pain and discomfort for trans-adolescents of going through the physical changes puberty. This year the NIH launched the largest longitudinal study on long-term psychological and medical effects of puberty suppressors, a drug for sex reassignment therapy for adolescents with gender dysphoria1.

Gender dysphoria was introduced in the DSM-V in 2013 as a condition in which an individual feels distress towards the sex and gender that they are born with; in previous versions of the DSM (DSM IV) this disorder was categorized as Gender Identity Disorder (GID). The name of the diagnosis was changed to reduce stigma and emphasize that gender non-conformity is not a disorder, but that the distress associated with it should be medically addressed. Many individuals with gender dysphoria elect to undergo hormonal and surgical treatments to obtain the body that matches their gender identity. Several studies have shown that these treatments lead to a decrease in gender dysphoria6. Adults undergoing sex reassignment therapy are generally treated with Cross-Sex Hormones (CSH) to induce secondary sexual characteristics of the sex they identify with. This therapy is still considered elective, is not covered by most insurance companies in the US, and most often the legal age to undergo it is the age of 16 (some countries set the cutoff at the age of majority).

This poses a problem for individuals under the age of 16 that experience gender dysphoria, because of the non-reversibility of CSH therapy, this treatment is not administered to them. However letting trans-adolescents go through puberty in their natal sex can be extremely painful for them, and makes transitioning in adulthood more challenging as certain secondary sexual characteristics need to be reversed (e.g. breasts, facial hair, voice tone). Studies have shown that gender dysphoria in prepubescent children is only maintained at adulthood in approximately 75% of cases1. Identifying with a sex other than the one you’re born with during adolescence almost always leads to wanting to pursue sex reassignment later in life4. This consistency has fueled much debate on how to treat trans-adolescents. The main pharmacological options currently are: withholding treatment during puberty and administering CSH after age of majority, treating adolescents with CSH (directly inducing the sex they identify with), or treating them with puberty blockers in early adolescence before CSH therapy.

Since a pilot study carried out between 2000 and 2008, trans-adolescents are eligible for treatment with GnRHa puberty blockers (Gonadotropin Releasing Hormone analogs)4. GnRH induces the release of follicle stimulating hormone and luteinizing hormone, which in both females and males regulate the expression of sex hormones (androgens and estrogens). GnRH analogs act as antagonists on the hormone receptors. This therapy offers a great advantage as sexual maturation in the preferred sex can then be induced by CSH treatment after the age of majority (or age of consent), and the adolescent is given more time to explore and understand his/her gender identity before undergoing permanent sex reassignment therapy.

Despite the apparent advantage of puberty blockers, the issue is highly controversial as ethical concerns and urgency to provide relief to trans-teenagers are contrasted by very little knowledge of the effects of the hormone antagonists. The NIH study (carried out by researchers at UCSF, Northwestern University and Boston Children’s Hospital) will be the first study to compare trans-adolescents undergoing GnRHa or CSH therapy to determine which course of action is more psychologically and medically favorable. Only one other long-term longitudinal study2 (in the Netherlands, 2014) has looked at the effects of GnRHa treatment on mental health in adulthood. This study showed that GnRHa therapy was successful in allowing teens to more easily transition (i.e. improved socio-psychological condition during and following puberty) to their preferred sex after CSH therapy was initiated at the age of 162. Gender dysphoria in these individuals was not alleviated until sex reassignment therapy was administered.

While GnRHa’s are successful in their goal to facilitate transition, it is unknown how they may affect other psychological and medical aspects of the trans-adolescent's life. Hormones are not only crucial for sexual development, but impact the development of our bodies and brains as a whole. An increase in the probability of breast cancer and bone brittleness is the main physical health concern that will be investigated in the NIH study. The study will also investigate the effects of GnRHa's on the feeling of gender dysphoria, and on general socio-psychological health. In the brain, as well as in the rest of the body, gonadal hormones are linked to more developmental processes than just sexual maturation. Particularly sex hormones have long been studied for their role in neural protection and regulation of neuronal cell death during development. Hardly any data is available in humans for the effects of GnRHa therapy, but animal studies on exposure to endocrine disruptors during development indicate possible effects on cognition and stress-coping skills3.

From a neuroscience perspective, trans-sexuality and its treatments pose more questions than we have answers for. Twin studies have indicated that gender dysphoria has some genetic basis5, though no further link has been made to specific chromosomes or loci. The occurrence of gender dysphoria is also thought to be affected by prenatal hormone exposure. Furthermore, the transition from childhood to puberty has been shown to be a time in which gender dysphoria either exacerbates and consolidates, or mitigates4 suggesting a sensitivity of the disorder to hormone levels.

More detailed research into the neural mechanisms of gender dysphoria and its treatments during adolescence and adulthood are hindered by the difficulty of studying it in any other system but humans. Other animals have long been studied for their sexually dymorphic (different in the two sexes) traits. These include parental behaviors, aggression, nesting, and sexual approach. Could the display of these behaviors by the two sexes be used to assay the effect of hormone therapies such as GnRHa and CSH during development? Animal studies on endocrine disruptors showed that socio-sexual behaviors (playing with peers, sexual approach to mates), and parental behaviors were affected, as well as cognitive and stress-coping skills3. Interestingly some of these behaviors were then conserved across generations, pointing to a possible component in the regulation of sexually dymorphic traits. Beyond the neuro-endocrine mechanisms at play during the 'exploratory period' of GnRHa's treatment, we must consider the environmental and social aspect of this transition. The peers of trans-adolescents will be undergoing puberty while they are not, and may be more resistant to understanding the development of gender-fluidity.

In neuroscience, development is often parsed into a series of critical periods, or windows of time, during which the brain is particularly plastic and is shaped into its adult, less plastic state. Puberty can be described as a critical period for mental and physical socio-sexual development. Hormone therapies can therefore alter delicate balances in the body in ways that are not reversible. Similar concerns can be raised for other hormone treatments and psychoactive drug administrations during childhood and puberty. If the puberty blockers or hormonal therapies prescribed for teenage gender dysphoria are shown to put these individuals at mental and physical risk, we shall be faced with the greater challenge to find other ways to care for the mental health of these individuals.